PROJECT SUMMARY With an incidence of one in 700-1000 live births worldwide, Down Syndrome (DS), or trisomy of human chromosome 21 (Hsa21), is the most common chromosomal abnormality. While DS is most often recognized for intellectual disability, congenital malformations, and dysmorphic features, it is also associated with seriously increased rates and severity of respiratory tract infection (RTI). Indeed, infectious respiratory disease in those with DS accounts for 54% of hospital admissions and more deaths than any other medical condition. Children with DS have a 62-fold higher rate of pneumonia than children without DS. During the influenza A (H1N1) pandemic in 2009, 23% of hospitalized patients with DS died vs. only 0.1% of those without DS. Collectively, these data point to an urgent need to understand how the condition of trisomy 21 contributes to RTI and to identify potential therapeutic targets. Currently, RTI in DS is commonly attributed to congenital abnormalities of the nasopharynx and upper and lower airways. However, our preliminary data support the novel hypothesis that lung immune cell dysfunction is a primary driver of increased incidence and severity of RTI in DS. Our data show that the trisomic Dp16 mouse lung is in a state of interferonpathy and is deficient in bronchus-associated lymphoid tissue (BALT). BALTs are key controllers of a variety of immune and inflammatory responses to numerous stimuli, including RTI. These changes in the Dp16 mouse lung closely mimic the dysregulated cytokine response in the human lung that has long been observed following influenza infection, and is a state linked to increased susceptibility to lethal bacterial pneumonia. Importantly, Dp16 mice are trisomic for the Hsa21-encoded interferon receptors and interferon-responsive genes. Based on these data, we propose to test our hypothesis that the constitutive activation state of interferon signaling in the DS lung reduces BALT biogenesis thus imparting immune suppression and predisposition to respiratory infection with S. pneumoniae. This state phenocopies the increased susceptibility to and severity of S. pneumoniae respiratory infection that is observed in typical individuals after a course of viral infection. The high mortality of RTI combined with poor response to vaccination is an urgent medical need in DS. Our novel paradigm conceptualizes DS as an interferonopathic state of heightened susceptibility to RTI due to depressed BALT function that mimics the state of acute viral infection in the typical population. In direct response to the NIH INCLUDE RFA, our proposal is a proof of concept study in an animal model of DS with high potential payoff that aims to enable efficient and effective movement of candidate therapeutics towards clinical trials for Down syndrome and RTI.